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. 2018;61(2):553-560.
doi: 10.3233/JAD-170777.

Co-Expression of Glia Maturation Factor and Apolipoprotein E4 in Alzheimer's Disease Brain

Ramasamy Thangavel  1   2 , Sachin M Bhagavan  1 , Swathi Beladakere Ramaswamy  1 , Spurthi Surpur  1 , Raghav Govindarajan  1 , Duraisamy Kempuraj  1   2 , Smita Zaheer  1 , Sudhanshu Raikwar  1 , Mohammad E Ahmed  1 , Govindhasamy Pushpavathi Selvakumar  1   2 , Shankar S Iyer  1 , Asgar Zaheer  1   2
Affiliations

Co-Expression of Glia Maturation Factor and Apolipoprotein E4 in Alzheimer's Disease Brain

Ramasamy Thangavel et al. J Alzheimers Dis. 2018.

Abstract

Apolipoprotein E4 (ApoE4) is a major genetic risk factor for Alzheimer's disease (AD). The E4 allele of ApoE plays a crucial role in the inflammatory and neurodegenerative processes associated with AD. This is evident from the multiple effects of the ApoE isoforms in amyloid-β (Aβ) aggregation. Glia maturation factor (GMF) is a brain-specific neuroinflammatory protein that we have previously demonstrated to be significantly upregulated in various regions of AD brains compared to non-AD control brains and that it induces neurodegeneration. We have previously reported that GMF is predominantly expressed in the reactive astrocytes surrounding amyloid plaques (APs) in AD brain. In the present study, using immunohistochemical and dual immunofluorescence staining, we show the expression and colocalization of GMF and ApoE4 in AD brains. Our results show that ApoE4 is present within the APs of AD brain. Further, we found that GMF and ApoE4 were strongly expressed and co-associated in APs and in the reactive astrocytes surrounding APs in AD. An increased expression of GMF in APs and neurofibrillary tangles in the AD brain, and the co-localization of GMF and ApoE4 in APs suggest that GMF and ApoE4 together should be contributing to the neuropathological changes associated with AD.

Keywords: Alzheimer’s disease; amyloid plaques; apolipoprotein E4; neurofibrillary tangles; neuroinflammation.

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Figures

Fig. 1
Fig. 1
ApoE4 expression is enhanced in AD brain and localizes with APs. (A) Co-localization of ApoE4 positive (brown color, white arrows) and thioflavin-S (green color arrowheads) revealed APs in temporal cortex of AD and non-AD brains. Merged image shows most of the APs extensively immunoreactive to ApoE4 are co-localized with thioflavin-S labeled APs. Magnification: 200x. (B) The data were expressed as mean ± SEM. P <0.05 versus non-AD was considered statistically significant.
Fig. 2
Fig. 2
Dual immunohistochemical staining reveals enhanced expression of GMF and ApoE4 in AD brain. (A) Double immunohistocehmical analysis of GMF (SG vector, blue/gray color, arrowheads) and ApoE4 stained APs (DAB, brown color, arrows) in temporal cortex of AD and non-AD brain. Magnification 200×. (B) Quantification of number of GMF and ApoE4 positive cells. The data were expressed as mean ± SEM and P <0.05 versus non-AD was considered statistically significant.
Fig. 3
Fig. 3
Co-localization of GMF and ApoE4 in the temporal cortex of human AD brain. (A) Co-localization of GMF (green color) and ApoE4 (red color) in the temporal cortex of AD and non-AD human brain. Sections were stained with anti-GMF and anti-ApoE4 antibody respectively to check the co-localization of GMF with ApoE4 in the temporal cortex of human AD brain. Magnification 200×. (B) Quantification based on average staining intensity and positive area. The data were analysed as mean ± SEM and P <0.05 versus non-AD was considered statistically significant.
Fig. 4
Fig. 4
Co-localization of GMF (A, green color) and ApoE4 (B, red color) and merged image (C, yellow color) indicates overlap of green and red in temporal cortex of AD brain. In addition, it shows that the ApoE4 positive APs was observed near clusters of reactive astrocytes. Magnification 200×.
Fig. 5
Fig. 5
ApoE4 and GMF are localized to regions of reactive astrocytes in temporal cortex of human AD brain. (A) Co-localization of GFAP (green) and ApoE4 (red) in human AD and non-AD brain. Representative immunofluorescence staining showed the co-localization of GFAP with ApoE4. Magnification 200×. (B) Quantification based on average staining intensity and positive area. The data were analysed as mean ± SEM and p <0.05 versus non-AD was considered statistically significant.
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